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Evaluation of the Threshold of Toxicological Concern (TTC) – Challenges and Approaches


Regulatory Toxicology and Pharmacology. 2013;65(1):168-177

Report of a workshop held on 8-11 June 2011 in Brussels Belgium.

Thresholds of Toxicological Concern (TTCs) have been used in the risk assessment of chemicals to which humans are exposed at very low levels. The TTC approach, however, should not be considered an alternative to testing procedures required for regulatory approval. TTC values were developed using the rodent bioassay cancer database of Gold and colleagues (see Gold et al., 2005), the non-cancer database of Munro et al. (1996a) and the decision tree of Cramer et al. (1978), which links general structural class to potential for toxicity. The Workshop assessed the adequacy and fitness for purpose of the TTC approach and the potential for future modifications of critical aspects. The current scheme for the endpoint of cancer was considered adequate and fit for purpose because it is based on the largest available rodent carcinogenicity database and is highly conservative as the TTC value is derived by linear extrapolation from the lowest TD50 for each compound while human relevance is not considered. The Munro et al. (1996a) database on non-cancer endpoints was considered adequate and fit for purpose because the chemical domain is comparable to other databases and the distributions of NOAELs and calculated TTC values for different Cramer et al. classes are similar to those derived from other databases. In addition, application of the TTC approach to different endpoints and different groups of chemicals gives conclusions compatible with the risk assessment approaches currently used by international advisory committees. Classification by the Cramer et al. (1978) decision tree is based on the single potentially most toxic functional group present in the molecule and most chemicals are assigned to the class with the lowest TTC value. The Workshop recognised the desirability of developing better tools to assess the comparability of the chemical domain covered in different toxicological databases, and the need to develop an internationally acceptable framework and databases for updating the aspects critical to application of the TTC approach.

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